1. Field of the Invention
This invention relates to the use of low energy radiation as a treatment for cancer and other conditions.
2. Description of Prior Art
Radiation Therapy for Targets in Proximity to Treatment Device
Radiation therapy has been a very successful and well-utilized means for controlling and sometimes even curing cancer. Most commonly delivered in an outpatient setting over several weeks, RT is delivered usually using machines capable of delivering high energy photons (megavoltage, MV) in a very controlled manner using ancillary devices such as multileaf collimators, intensity modulating delivery paradigms, and portal imaging systems for monitoring treatment delivery. Since the high energy of the x-rays generated by these machines can penetrate very deeply, these machines can be used to treat tumors occurring deep inside the body.
Superficial Cancers
Unfortunately, sophisticated MV delivery systems may not be able to treat superficial cancers such as those of the skin or nonmalignant lesions of the skin such as keloids. This inability to treat superficial lesions is due to the nature of the differential dose deposited at depth with MV energy x-rays; these x-rays deliver a much lower dose within mm to cm of the surface than they do at depth due to the buildup of dose from scattered electrons as the beam passes through tissue. Thus it is difficult to deliver enough dose near the skin surface without overdosing tissue lying under the skin.
MV delivery systems also may not be applicable for use in the treatment of tumors that receive radiation therapy at the time of surgery. Called intraoperative radiation therapy (IORT), this special technique permits the application of a high dose of radiation during surgery. The possibility of manually moving healthy organs situated in between of the radiation beam and the target out of the beam path reduces the toxicity of the therapy. In addition, the possibility of directly visualizing the area of intervention improves the degree of precision inherent in the administration of the radiation dose. IORT offers several advantages: it may eliminate post-surgery residual tumor; offer an intensification of the antitumoral effect of the radiotherapy in that it permits the administration of a higher dose of radiation than would otherwise be possible with external beam irradiation; reduce the time lapse between the surgical removal and the irradiation, a period of time during which residual cellular clones can grow.
Intraoperative Radiation Therapy
IORT ideally should be given in the operating room (“OR”). However, conventional MV radiation equipment is very heavy and large and requires thick concrete walls to contain the stray radiation produced by the equipment. This has restricted OR-based IORT to a handful of hospitals that have been able to absorb the high costs associated with the equipment and the construction of large shielded room in the OR. Most other hospitals throughout the world that conduct IORT do so by performing the operation in the OR and then transporting the patient, still under anesthesia and with the surgical site open, to the radiation facility for the radiation portion of their treatment. After the radiation treatment is completed, the patient is then transported back to the OR for the completion of the operation. This method of IORT involves very complex logistics, increases patient risk, severely limits the number of patients that can be treated, and reduces the potential efficacy of the treatment.
Other Approaches
MV devices have a range of other problems as well. Ranging in price from $1 M to in excess of $4 M depending on features, external beam megavoltage delivery devices are very complicated to build and are quite time consuming when it comes to creating a plan for delivering the treatment and in actually delivering the treatment. They require very controlled environments (temperature, power, and humidity) in which to operate and must be installed in specially designed and shielded rooms in order to protect personnel from stray radiation. They require constant and expensive maintenance and monitoring, suffer from significant downtime, and only can be used by highly trained personnel working in dedicated departments.
As a result, a variety of techniques have been developed or are being explored to improve the delivery of a tumorcidal dose of radiation to superficial lesions either in an outpatient or intraoperative setting. Electrons, rather than x-rays, can be used for superficial skin treatments. Generated by the same megavoltage machines as x-rays, electrons pass less deeply into tissue and therefore have been used to treat superficial lesions. Electrons also can be used to deliver radiation to a tumor bed while the patient is undergoing surgery. Recently mobile IORT treatment units have been developed that can be used directly in an OR. These units are electron-based, and therefore require minimal shielding. Because the treatment is delivered in the OR the biological effectiveness of the treatment should be improved through their use.
Their major disadvantages are that they are not as easy to characterize and plan for as are photons and they add cost to the price of the already expensive MV device (which is used to generate them). They also have limitations when used to treat lesions that are directly under the skin surface. In terms of IORT, although much more mobile and user friendly than their predecessors, mobile electron units still weigh close to one ton and are large and ungainly, making it difficult to move them around in an OR and bring them in opposition to the treatment site, and are expensive in terms of user and patient time. They also are relatively imprecise in terms of their ability to treat irregularly shaped tumors and are quite time-consuming to plan for and use.
Low Energy Therapeutic Radiation
Kilovoltage x-ray units and orthovoltage devices also have been used to treat superficial tumors and other abnormalities. Whereas MV devices deliver x-rays with an energy of 1 MV to 20 or more MV, superficial machines deliver kilovoltage (KV) x-rays with an energy of about 20-80 KV (orthovoltage machines operate at 150-400 KV). These devices are low cost, easy to build, and can be made very compact (with a tube as small as several mm in diameter). In addition, they can be used easily and cheaply to image the patient at the same time the patient is being treated, allowing localization of the target and monitoring of the impact of treatment. Because they are low energy they require very little in the way of user and patient shielding, making them able to be installed in almost any environment, increasing safety and reducing significantly the cost of building a treatment facility.
The major downside to low energy x-rays that has limited severely their use in modern day cancer treatment is that they have very poor penetration in tissue. Superficial machines are designed to treat to a depth of 1-3 mm and orthovoltage machines to a depth of 3-20 mm (both ranges depend on energy). They have also a surface dose that is as much as a hundred times more than the dose at depth resulting in the potential for severe skin reactions when treating deeper lesions. As a result therapeutic low energy x-rays delivered by traditional means are very limited in their applications.
One approach that has been explored for improving this situation is to deliver the low energy x-rays in a rotational fashion such as with a CT scanner. When an x-ray source is rotated about the target with the target at the center of rotation, different portions of the skin are subjected to the x-ray beam as it is directed to the isocenter. This keeps the overall skin dosage at any one location relatively low compared to the concentrated dose at the target. This approach has been explored for use in radiosurgical treatments but is severely limited for superficial applications. Rotational treatments are only as good as the extent of the angle of rotation—the greater the solid angle of rotation, the greater the range of delivery positions of the x-rays relative to the position of the target, thus the greater the dose at depth and the lower the skin dose. The best results are achieved when the x-rays can be rotated through as many as 360 degrees or more. Unfortunately, because the depth of penetration of KV x-rays is so poor, there are limited geometries that can be used through which to rotate the beam for superficial target locations, resulting in only several degrees of rotation and therefore very little increase in dose at depth or lowering of skin dose.
Another approach that has been used to improve the effectiveness of KV x-rays involves the use of optically focused beams. A series of mirrors are used to redirect KV x-rays such that they are concentrated in a spot at depth in tissue. By so doing, the dose to skin is reduced, the depth at which dose is possible is increased, and the rate at which dose is deposited at depth is increased. Perhaps as important for very small lesions, the dose falloff can be very sharp at the edges of the treatment field. Effective at achieving the desired goals, this approach requires the construction of a complex focusing system. Although such can be designed as an add-on device to an existing orthovoltage systems, it increases the cost very significantly and prices it out of the reach of practicing physicians. It also is quite inefficient, as the reduction in skin dose and the increase in treatment depth and dose rate at depth are achieved by concentrating the x-ray beam at a very small spot, the gains being proportional to the decrease in spot size. Thus larger lesions would need to be treated by scanning the spot across the target, achieved either by moving the patient under the delivery device or by mounting the delivery device in such a manner that the spot can be scanned over an immobilized patient; either approach adds considerably to the cost of the overall system. When this is performed, the approach also looses much of its sharp dose fall-off at the beam edges. In addition, it is not meant to treat superficial lesions; the process of focusing the dose would result in a potential increase in skin dose if the treatment were delivered to a superficial location. Finally, this system, like all other radiation therapy systems, requires extensive preplanning and control over patient position in order to insure that the correct dose is delivered to the correct location within the patient.
Devices for delivering low energy x-rays also can be inserted directly into the region in question in order to deliver a turmorcidal dose, or can be delivered to a deep location by a needle that is delivered to the tumor by percutaneous puncture or by passage through a lumen or hollow viscus. This approach also is plagued by the problems inherent to date in using low energy x-rays, namely the dose where the x-ray beam first enters tissue at the center of the volume being treated is very much greater than the dose in the rest of volume being treated. Attempts have been made to mitigate this problem by using multiple electronic x-ray sources or multiple positions of a single x-ray source but this increases the invasiveness of the procedure.
Radioactive isotopes also can be used to treat deep volumes and can be used as well to treat superficial lesions and to treat the cavity exposed at the time of surgical resection. This can be done by shielding the isotope to control the direction in which the radiation is delivered and then passing the isotope through channels contained in a matrix that is laid on the skin surface or in the resection cavity. However, the problem with radioactive isotopes is the same as with KV or low energy radiation—the dose is very much higher at the point(s) where the dose enters the tissue than at any other place. This makes it very difficult to deliver a uniform dose to a thickness of tissue or to deliver a dose at depth that is greater than the dose delivered to the tissue surface.
Target Identification
There also are problems associated with defining the region to be treated and to making sure that the correct region is treated. Typically, patients are imaged with CT or MR or ultrasound in order to identify the target volume. The images generated from these procedures are usually transferred into a treatment planning system where the target volume is outlined. It is then required that the patient position at the time of treatment be registered to the patient position at the time of imaging so that the treatment plan, created for a target volume spatially defined based on the patient position at the time of imaging, is correct based on the patient position at the time of treatment. This is a process that, because of its complexity and the difficulty in positioning patients, is prone to error.
Need
Thus what is needed is a low cost system using low energy radiation that can treat regions of tissue of variable depth in a range of locations in a patient, such as regions on or below the surface of tissue, in a cavity and the underlying region created following a surgical resection, on or below the surface of an internal cavity, hollow viscus, or lumen, or deep in tissue adjacent to an inserted probe or conduit or catheter, by delivering a dose at depth that is equal to or greater than the dose at the point of radiation emission without the need to preimage the patient or preplan the treatment and in an automatic fashion such that the practitioner is released from the requirement of guiding and delivering the treatment in a manual fashion, thereby improving accuracy and outcome, increasing the access of patients to such treatment, and decreasing the risk to the user.
Targets Deep to the Delivery Device
The Need
In addition to the need for new apparatus and methods for treating superficial lesions or lesions in close proximity to the radiation delivery device there also is a need for new apparatus and methods when treating tumors that are deep to the tissue surface or that are not accessible by a needle or that are disseminated diffusely in tissue. The theoretical goal of any intervention for cancer, especially for such tumors, is to eliminate malignant cells without effecting normal tissue. This is only theoretical because all known therapies have side effects that limit their usefulness. This is especially the case for radiation therapy.
It is well known that any cancer cell can be killed if subjected to a high enough single dose of radiation. Such single session treatments also are attractive to patients because if the limited amount of time they need to spend receiving treatment. A specialized radiation therapy delivery technique called radiosurgery has been developed so that the dose that can be delivered to deep targets can be increased such that certain targets can in fact be treated in a single session. This is accomplished by moving the x-ray source patient; a series of exposures in which the beam is aimed at the tumor from different directions, including a series of rotational arcs, will keep a high dose on the tumor while spreading dose to healthy tissue over a much larger volume, significantly reducing dose to the healthy tissue.
However, because this single dose of radiation also will kill all surrounding and interwoven normal cells within the treatment field, it is limited currently in the types of tumors it can treat. Also, its cost, believed to cost in excess of $5 M for equipment, room, and specialized supporting infrastructure, limits its availability. As a result of the clinical and limited access issues, most radiation therapy is delivered using a large number of small doses (fractions). This approach is less effective (in terms of malignant cell kill) and takes more time (multiple treatments over weeks versus a single treatment on a single day) but is safer (in terms of normal tissue function) because normal cells receive less dose per treatment. Since normal cells effectively are marginally less affected by radiation than malignant cells, the cumulative effect of the radiation over time is to destroy cancer cells while allowing normal cells to continue to function.
Unfortunately, the marginal difference between the effect of radiation on malignant cells and normal cells is not great enough to allow radiation to be delivered to both regions indiscriminately, even with fractionation without incurring serious side effects. As a result much time and effort has gone into designing equipment and creating delivery techniques that allow the greatest possible physical separation between normal and malignant cells so that the normal cells will receive less radiation than the malignant cells. The most modern of these techniques (intensity modulated radiation therapy (IMRT), image guided radiation therapy (IGRT), high dose rate remote afterloader brachytherapy) try to conform the high dose of radiation to the region of malignant disease while avoiding delivering dose to as much normal tissue as possible.
However, modern day radiation therapy may have reached its limit in terms of its ability to eliminate or control cancer, especially for invasive cancers where the malignant cells intermix with normal cells such that killing the former also will kill the latter. Even with IMRT it is impossible to create a conformal enough dose distribution such that all cancer cells are destroyed but all normal cells are spared. IGRT reduces the amount of normal tissue that is included in the treatment volume but cannot eliminate it entirely. Although metabolic imaging techniques can provide additional information about cancer location, the designation of a target volume is still a physician-based process, fraught with inter- and intra-user variability and with an inability to differentiate disease from normal at the cellular level. In addition, many cancers contain radioresistant regions in their center due to poor oxygenation. It is not until the surrounding well oxygenated cells are destroyed that oxygen can be delivered to the interior, thereby making these cells more radiosensitive. However, the amount of radiation required to kill the initial group of oxygenated cells uses up all of the normal tissue reserve; the interior cells once oxygenated cannot be treated with additional radiation without destroying surround normal tissue.
Thus it is possible that without a paradigm shift in the way radiation therapy is delivered the physician-defined target-directed radiation therapy of today probably is nearing its maximum capability as a cancer-fighting therapy.
Binary Therapy
The limited efficacy and extended toxicity of traditional single agent cytotoxic therapy such as radiation therapy has led researchers to explore the design and development of targeted binary therapies that differentiate between, and thereby augment the effect on, malignant cells as compared to nonmalignant cells. A binary therapy is an approach that utilizes two agents, each of which by itself has no cytotoxicity but when used in concert become tumorcidal. In theory, if one or both of the two agents can be restricted to the cancerous cells only, then the therapy can have an extremely high therapeutic ratio (ratio of dose delivered to tumor versus dose delivered to tissue) with much less toxicity than conventional therapies.
A number of binary therapies are under development; those based on or including the use of radiation often are called radiogenic therapy. Although external beam MV radiation is being explored as a means of activating chemotherapeutic agents (an inactive “prodrug” is converted to an active drug by the MV radiation) or gene vectors (an antitumor “pro-gene” injected into the tumor is converted to an active gene by MV radiation), it is believed that one of the more promising approaches is based on the principle of dose enhancement through Auger electron emission.
When an x-ray encounters an atom, it interacts through one of three processes: photoelectric absorption, elastic scattering, or Compton scattering. The relative probability of each interaction is a function of the x-ray photon energy. In Compton scattering, an incident photon loses enough of its energy to an outer orbital electron to cause its ejection. This electron has an energy equal to that lost by the photon as a result of the interaction, and can be quite sizeable. The original photon continues on its way but in a new direction, with a lower energy, and with the potential to interact again at any distance. Compton scattering is thought to be the principal absorption mechanism for x-rays in the normal therapeutic range of 100 KeV to 10 MeV (million electron volts) and is relatively independent of the atomic number of the absorbing material.
The photoelectric effect is the most efficient means for conversion of x-ray energy to ionization in the body and is believed to dominate at low energy (10-120 KeV). It is a process whereby a photon, of an energy near the absorption energy of an inner electron shell in the target material, transfers its entire energy to the electron that subsequently is ejected from the atom (photoelectron). The relatively low kinetic energy of the ejected photoelectron is equal to the incident X-ray photon energy minus the binding energy of the electron. The vacancy in the electron orbital resulting from the electron ejection is filled by an electron from an outer orbit (with a lower binding energy), leaving a vacancy in this outer orbit that in turn is filled by another electron from an orbit even further away from the nucleus. The surplus energy liberated when an electron drops from an outer shell to a shell closer to the nucleus results either in the emission of a fluorescent photon or in the ejection of an additional secondary electron (Auger electron) from the same shell. If Auger electron emission occurs, the atom is left in a doubly ionized state (due to two ejected electrons) that is resolved by the dropping of other electrons from outer shells to fill the holes. This cascade process results in the release of a large number of very low energy electrons that travel very short distances and deposit their energy (track ends) locally (therefore with a very high linear energy transfer (LET)). If the electrons are produced near the DNA they can be very effective in killing the cell through double strand breaks.
The depth of penetration of Auger electrons is very small, on the order of 1-10 micrometers. Thus reliable cell death requires that the Auger electron be generated within 1-10 micrometers of the DNA, e.g. within the cell (and preferably within the nucleus) itself. The disadvantage of this approach is that the process for generating the Auger electrons must take place within the cell. The advantage is that the tumorcidal effect of the radiation is limited to the target cells. As a result, such a therapy has the potential for repetitive dosing with minimal toxicity.
Dose Enhancement
Auger electrons at a target site can be increased significantly if a high Z material is introduced into the target as long as the energy of the radiation is at or near the K, L, or M electron shell binding energies for the high Z material. The radiation interacts with the high Z material that, because of the energy match between the radiation beam and the material's greater density of electrons (as compared to tissue), produces auger electrons in great numbers. This process is known as dose enhancement; the local deposition of dose is increased due to the presence of a high z material. Dose enhancement with high Z materials is minimal or absent at high radiation energies because of the limited number of photoelectric interactions that occur at megavoltage energies due to the fact that the binding energy of high Z materials are in the low energy range.
Depending on the element, concentration of element, and low energy photons used, the local dose may be increased by as much as 150 fold or more. Contrast material has been used traditionally as the dose enhancement agent in conjunction with orthovoltage x-rays in order to produce an increase in the level of dose by a factor of 0.5 to as much as 2 or more depending on energy and concentration of agent in the tissue (the higher the concentration, the greater the dose enhancement). Contrast agents contain typically a large percentage of a heavy element from the upper half of the periodic table such as iodine or gadolinium; it is the interaction of the othovoltage x-rays with the element that results in the dose enhancement. Because tumors usually contain “leaky” blood vessels, contrast material injected in the vascular system will find its way into a tumor through extravasation from these blood vessels. In fact historically, it is the region of contrast enhancement that is designated as the target volume for radiation therapy treatments.
It is important to note that contrast agents identify regions of disruption of vascular and by extension indirectly identify regions that may contain cancer cells. However, these agents do not identify cancer cells directly. Thus by using a contrast agent alone to generate dose enhancement, it is possible not only to kill normal cells contained within the region of contrast enhancement but to not identify cancer cells that lie in regions that do not enhance, or where the concentration of cancer cells is too small to cause vascular disruption. In addition, it is often difficult to deliver enough contrast agent to the region in question by the IV route in order to achieve significant enough dose enhancement. Direct injection allows for a higher concentration of contrast agent, but it requires an invasive procedure that may not gain access to all tumors.
There are other materials that have been explored for dose enhancement with radiation of all types, namely gold particles of any size, and other ways of delivering the particles to the tumor so that only abnormal cells are labeled or are labeled preferentially, namely using antibodies, oligonucleotides, nucleotide analogues, amino acids, and dendrimers. Gold nanoparticles are inert and biocompatible and the gold surface provides a simple chemistry for the self-assembly to labeling materials thereby encouraging the nanoparticles to accumulate in the vicinity of, or directly inside, malignant cells. They can be delivered by IV injection or sprayed/injected directly onto/into the target (if accessible) and can accumulate in concentrations sufficient to blanket all cells in the target volume. Gold nanoparticles, when used in the presence of 50 kvp radiation, are predicted to result in a dose enhancement of as much as 150 fold based upon published studies performed with thin gold foil. However, the actual enhancement able to be obtained in a clinical setting is dependent on the percent of the total mass contributed by the gold. With reasonable levels of 0.3-3% that are obtainable clinically, an enhancement level believed to be on the order of 2-10 fold can be expected.
The differential dose enhancement of tumor cells versus normal tissue only occurs if the high Z material is linked to tumor cells and not to normal cells. Means for achieving such in the past have centered on the use of contrast agents; the agent leaks out of highly permeable vasculature in the tumor to stain the tumor and not surrounding normal tissue possessing normal vessels. However, ideally one would like to target the tumor cells directly, thereby allowing direct differentiation between normal and abnormal cells. Since the enhanced effect from Auger electrons are believed to occur predominantly in the cells where they are generated, direct targeting of abnormal cells could allow the destruction of an abnormal cell while sparing an immediately adjacent normal cell.
Problems with Low Energy Radiation
The major downside to low energy x-rays that limits their use in dose enhancement applications is their very poor penetration in tissue as described previously. At a depth of 20-30 cm, the residual dose from a 50-70 KV beam, the optimal energy range for gold dose enhancement, is about 0.001-0.1% of its maximum dose; even at a maximal 10× enhancement no more than 1% of the maximum dose at the surface will be delivered at depth. This can be improved by using multiple fields to deliver the treatment, such as is used in radiosurgery, thereby spreading the dose to nontarget tissue out over a larger area. However, even using 10 fields will only result in a dose at depth that is at best equal to 10% of the dose at the skin.
A range of approaches such as optically focused beams and rotational x-ray sources have been used to increase the dose of low energy radiation deposited in deep targets that would interact with dose enhancement agents; these were described previously. Unfortunately, the same problems discussed previously that apply to each of the low energy x-ray delivery approaches without the use of dose enhancement apply to their use with dose enhancement, namely a high cost, complexity, a lack of portability, lengthy treatment times, and limited available geometries restricting applicability, apply when used with dose enhancement. Another approach that has been explored is with the use of a monenergetic beam of radiation produced by a synchrotron that is able to deliver the required radiation at a much faster rate. Unfortunately, this is a $100 million device based on a cyclotron that limits severely its availability and suitability.
Thus there still is a need to develop a realistic, practical, cost and time efficient, portable, universally available, easy to manufacture, and easy to use means of delivering in a single or few fractions to cancer cells deep in a patient a dose of radiation sufficient enough to be able to benefit from the dose enhancement possible with high z materials delivered selectively to the target without producing too much dose of radiation in other portions of the patient and especially at the tissue surface.